Australia went to lunch on day two on 2-115 in reply to England's first-innings 283, after a slow morning session that featured 41 runs off the bat.
Marnus Labuschagne was the one man out, falling victim to a superb one-handed diving catch by Joe Root at first slip on nine after wicketkeeper Jonny Bairstow didn't move.
Labuschagne soaked up 82 balls for his runs, in another sign of how different Australia have approached this Ashes series to England.
Khawaja is perhaps the greatest proof of Australia's readiness to do things their own way, after going to lunch unbeaten on 47 and overtaking Zak Crawley as leading run-scorer for the series.
The 36-year-old had arrived in England with question marks over his ability to survive in the conditions after averaging 17.78 in the UK before this series.
Khawaja thought his career was over when dropped during the 2019 Ashes, and was also axed on his maiden Test trip to England in 2013.
But in this series alone, Khawaja has now struck 414 runs at an average of 51.75 to lead Australia's charge for their first series win in England in 22 years.
The left-hander has also become the first Australian to face more than 1000 balls in an Ashes series this century, occupying the crease for 1095 so far.
That figure is almost double that of Ben Stokes' 559, who has faced the most for England.
Khawaja's scores of 141 and 65 at Edgbaston set up Australia's 1-0 lead in the series, while his second-innings 77 at Lord's was a big part of the tourists going 2-0 up.
He had underwhelming returns at Headingley and Old Trafford as Australia's lead was reduced to 2-1 but has returned to form in London.
The Queenslander's approach on Friday helped Australia's bid to grind England out of the Test, with Stokes and Moeen Ali both unable to bowl due to injuries.
Australia have already batted out 21 maiden overs at The Oval, nine more than England did at Headingley, Old Trafford and in the first innings of this match combined.
Among the few highlights of the morning were two back-to-back drives from Steve Smith (13 not out) off James Anderson before lunch, when the English veteran went too full.
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